The present invention relates to water-soluble compositions or complexes of certain water-soluble phosphonic acids and salts with certain water-soluble polyvalent metal salts, for use in the preparation of stable aqueous solutions containing radioactive .sup.99m technetium.
The invention includes the compositions of the phosphonic-polyvalent metal components in tableted dry mix and in aqueous solution forms. The invention also includes aqueous solutions of low valence .sup.99m technetium compounds having a content of said phosphonic-polyvalent metal compositions as stabilizer, and methods for the preparation of said solutions.
It has been known for some time that X-ray investigations for recognizing skeletal diseases and tumors, especially in the early stages, are not entirely satisfactory, even when effective treatment is possible. Newer methods have therefore been developed in which the radioactive isotopes fluorine-18 and strontium-85 are used, which are selectively adsorbed in the skeleton and in particular by diseased portions of the skeleton. These radioactive isotopes concentrate even in calcareous tumors. Bone or tissue diseases can then be recognized and their sites identified by radiography. The production of .sup.18 F, however, requires complex apparatus which is usually not present in hospitals and in addition .sup.18 F has an extremely short half-life (only 110 minutes). The isotope .sup.85 Sr, on the other hand, has a very long half-life (65 days), but this isotope requires very long scanning periods because of its slow rate of decomposition and consequent low radio-emission rate.
Because of these disadvantages, interest has recently been directed to the radio isotope technetium-99.sup.m, which has a half-life of 6 hours. Very convenient apparatus is available for its production, by which the isotope is obtained in the form of sodium .sup.99m pertechnetate by extraction with isotonic sodium chloride solution. In this form the technetium has a valence of 7.
The pertechnetate-.sup.99m ion differs from ions containing .sup.18 F and from .sup.85 Sr.sup.2+ in that in the body the pertechnetate ion is not specially bound in the skeleton or to calcareous tumors. It is therefore not practically useful for the scintigraphic examination of bones and calcareous tumors. In order to use it, therefore, the pertechnetium in the ion must be reduced to a relatively low oxidation state (i.e., to a low valence state) and then stabilized with a suitable complex former in this oxidation state. The valence of the technetium in this reduced state is 4. The complex former must also have a high selectivity for preferred adsorption by the skeleton or by calcareous tumors. Initial successes were achieved with certain polyphosphates whose complexes, however, have only moderate stability with low oxidation state technetium. A suitable complex was produced by mixing .sup.99m pertechnetate solution with an aqueous solution of ditin (II) ethane-1-hydroxy-1,1-diphosphonate (described in J. Nucl. Med. 13, 947 and 14, 73). The stability of this ditin (II) ethane-1-hydroxy-1,1-diphosphonate solution was restricted, however, with an excess of ethane-1-hydroxy-1,1-diphosphonate, especially since the tin (II) ion has a tendency to hydrolyze. A composition for the preparation of a material for the scintigraphic scanning of bones on this basis is described in German Patent Specification No. 2,424,496.
It has now been found that certain carboxy phosphonic acids and their salts are very desirable complexing agents because of the high stability of their complexes with ions containing low oxidation state technetium ions and because of the high selectivity with which the .sup.99m Tc deposits itself in the bone tissue or in calcareous tumors.